PROJECT SUMMARY Retinal detachment (RD), caused by injury or retinal disorders (e.g. age-related macular degeneration and diabetic retinopathy), is a leading cause of retinal degeneration and vision loss. Photoreceptor cell death in RD occurs due to physical separation of photoreceptors from the retinal pigment epithelium and choroid, which results in acute ischemia. Photoreceptors are energetically demanding, and are therefore highly susceptible to ischemia, rapidly developing mitochondrial dysfunction and degenerating in RD. Our exciting preliminary data has demonstrated that female mice are protected from RD-induced photoreceptor cell death, and that the female sex hormone estrogen may mediate this effect by supporting mitochondrial function under ischemic conditions. The central hypothesis of this application is that females are protected from RD-induced retinal degeneration through the actions of estrogen-dependent normalization and/or rescue of photoreceptor mitochondrial dysfunction. We will refute or validate this hypothesis through two interrelated but independent specific aims. Aim 1 is to determine which female sex hormone(s) are operative in RD sexual dimorphism, and to assess the role of systemic versus localized estrogen in neuroprotection from RD. Aim 2 is to elucidate the role of mitochondrial dysfunction in RD, and to determine if estrogen-mediated mitoprotection is operative in neuroprotection from RD. This study will yield new insights into the role of estrogen in retinal neuroprotection and identify new therapeutic targets for the clinical management of sight-threatening diseases such as RD.